No clinical utility of common polymorphisms in IGF1, IRS1, GCKR, PPARG, GCK1 and KCTD1 genes previously associated with insulin resistance in overweight children from Romania and Moldova

Abstract Background Previous genome-wide association studies (GWAS) identified IGF1, IRS1, GCKR, PPARG, GCK1 and KCTD1 as candidate genes for insulin resistance and type 2 diabetes (T2D). We investigated the associations of these previously reported common variants in these genes with insulin resistance in overweight children from Romania and Moldova. Methods Six single nucleotide polymorphisms (SNPs), IGF1 (rs35767), IRS1 (rs2943634), GCKR (rs780094), PPARG (rs1801282), GCK1 (rs1799884) and KCTD15 (rs29941), were genotyped in 100 overweight children along with clinical and metabolic parameters. Homeostatic model assessment of insulin resistance (HOMA-IR) above 3.4 (defining insulin resistance) was used as the outcome. Results Children differed in insulin resistance status despite having similar body mass index (BMI) standard deviation scores (SDS) (World Health Organization, [WHO] reference). The identified predictors for altered insulin metabolism were higher cholesterol levels, higher diastolic blood pressure and higher waist-to-hip-ratio (as a marker for increased abdominal fat). None of the SNPs showed significant association with increase in the risk for insulin resistance in children (p range=0.478–0.724; odds ratio [OR] range=1.924–4.842); however, the risk allele in GCKR (rs780094, p=0.06, OR=6.871) demonstrated near statistical significance. Conclusions The interrogated risk alleles did not show any significant association with insulin resistance in children in our cohort; however, the GCKR (rs780094) might be a viable candidate in larger cohorts. The lack of replication of the proposed association may point to differences in linkage disequilibrium or effect modifiers across studies.

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Associations of Two Obesity-Related Single-Nucleotide Polymorphisms with Adiponectin in Chinese Children

International Journal of Endocrinology ◽

10.1155/2017/6437542 ◽

2017 ◽

Vol 2017 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Lijun Wu ◽

Liwang Gao ◽

Xiaoyuan Zhao ◽

Meixian Zhang ◽

Jianxin Wu ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Multiple Testing ◽

Association Studies ◽

Statistical Significance ◽

Additive Model ◽

Recessive Model ◽

Chinese Children ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Single Nucleotide

Purpose. Genome-wide association studies have found two obesity-related single-nucleotide polymorphisms (SNPs), rs17782313 near the melanocortin-4 receptor (MC4R) gene and rs6265 near the brain-derived neurotrophic factor (BDNF) gene, but the associations of both SNPs with other obesity-related traits are not fully described, especially in children. The aim of the present study is to investigate the associations between the SNPs and adiponectin that has a regulatory role in glucose and lipid metabolism. Methods. We examined the associations of the SNPs with adiponectin in Beijing Child and Adolescent Metabolic Syndrome (BCAMS) study. A total of 3503 children participated in the study. Results. The SNP rs6265 was significantly associated with adiponectin under an additive model (P=0.02 and 0.024, resp.) after adjustment for age, gender, and BMI or obesity statuses. The SNP rs17782313 was significantly associated with low adiponectin under a recessive model. No statistical significance was found between the two SNPs and low adiponectin after correction for multiple testing. Conclusion. We demonstrate for the first time that the SNP rs17782313 near MC4R and the SNP rs6265 near BDNF are associated with adiponectin in Chinese children. These novel findings provide important evidence that adiponectin possibly mediates MC4R and BDNF involved in obesity.

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Association of GWAS-Based Candidate Genes with HDL-Cholesterol Levels before and after Bariatric Surgery in the Swedish Obese Subjects Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2010-2227 ◽

2011 ◽

Vol 96 (6) ◽

pp. E953-E957 ◽

Cited By ~ 21

Author(s):

Mark A. Sarzynski ◽

Peter Jacobson ◽

Tuomo Rankinen ◽

Björn Carlsson ◽

Lars Sjöström ◽

...

Keyword(s):

Bariatric Surgery ◽

Weight Loss ◽

Candidate Genes ◽

Association Studies ◽

Statistical Significance ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Cross Sectional ◽

Time Points ◽

Obese Subjects

Context and Objective: The magnitude of weight loss-induced high-density lipoprotein cholesterol (HDL-C) changes may depend on genetic factors. We examined the associations of eight candidate genes, identified by genome-wide association studies, with HDL-C at baseline and 10 yr after bariatric surgery in the Swedish Obese Subjects study. Methods: Single-nucleotide polymorphisms (SNP) (n = 60) in the following gene loci were genotyped: ABCA1, APOA5, CETP, GALNT2, LIPC, LIPG, LPL, and MMAB/MVK. Cross-sectional associations were tested before (n = 1771) and 2 yr (n = 1583) and 10 yr (n = 1196) after surgery. Changes in HDL-C were tested between baseline and yr 2 (n = 1518) and yr 2 and 10 (n = 1149). A multiple testing corrected threshold of P = 0.00125 was used for statistical significance. Results: In adjusted multivariate models, CETP SNP rs3764261 explained from 3.2–4.2% (P < 10−14) of the variation in HDL-C at all three time points, whereas CETP SNP rs9939224 contributed an additional 0.6 and 0.9% at baseline and yr 2, respectively. LIPC SNP rs1077834 showed consistent associations across all time points (R2 = 0.4–1.1%; 3.8 × 10−6 < P < 3 × 10−3), whereas LPL SNP rs6993414 contributed approximately 0.5% (5 × 10−4 < P < 0.0012) at yr 2 and 10. In aggregate, four SNP in three genes explained 4.2, 6.8, and 5.6% of the HDL-C variance at baseline, yr 2, and yr 10, respectively. None of the SNP was significantly associated with weight loss-related changes in HDL-C. Conclusions: SNP in the CETP, LIPC, and LPL loci contribute significantly to plasma HDL-C levels in obese individuals, and the associations persist even after considerable weight loss due to bariatric surgery. However, they are not associated with surgery-induced changes in HDL-C levels.

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Snp Characteristics and Validation Success in Genome Wide Association Studies

10.21203/rs.3.rs-704899/v1 ◽

2021 ◽

Author(s):

Olga Gorlova ◽

Xiangjun Xiao ◽

Spiridon Tsavachidis ◽

Christopher I. Amos ◽

Ivan P. Gorlov

Keyword(s):

Success Rate ◽

Association Studies ◽

Statistical Significance ◽

Positive Association ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Multivariable Logistic Regression Model ◽

Functional Studies ◽

Genome Wide

Abstract Genome wide association studies (GWASs) have identified tens of thousands of single nucleotide polymorphisms (SNPs) associated with human diseases and characteristics. A significant fraction of GWAS findings can be false positives. The gold standard for true positives is an independent validation. The goal of this study was to identify SNP features associated with validation success. Summary statistics from the Catalog of Published GWASs were used in the analysis. Since our goal was an analysis of reproducibility, we focused on the diseases/phenotypes targeted by at least 10 GWASs. GWASs were arranged in discovery-validation pairs based on the time of publication, with the discovery GWAS published before validation. We used four definitions of the validation success that differ by stringency. Associations of SNP features with validation success were consistent across the definitions. The strongest predictor of SNP validation was the level of statistical significance in the discovery GWAS. The magnitude of the effect size was associated with validation success in a non-linear manner. SNPs with risk allele frequencies in the range 30-70% showed a higher validation success rate compared to rarer or more common SNPs. Missense, 5’UTR, stop gained, and SNPs located in transcription factor binding sites had a higher validation success rate compared to intergeneic, intronic, or synonymous SNPs. There was a positive association between validation success and the level of evolutionary conservation of the sites. In addition, validation success was higher when discovery and validation GWASs targeted the same ethnicity. All predictors of validation success remained significant in a multivariable logistic regression model indicating their independent contribution. To conclude, we identified SNP features predicting validation success of GWAS hits. These features can be used to select SNPs for validation and downstream functional studies.

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No correlation between the variants of exostosin 2 gene and type 2 diabetes in Burkina Faso population

Journal of Public Health in Africa ◽

10.4081/jphia.2020.1233 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Serge Yannick Ouedraogo ◽

Daméhan Tchelougou ◽

Jonas Koudougou Kologo ◽

Herman Karim Sombie ◽

Moutanou Modeste Judes Zeye ◽

...

Keyword(s):

Type 2 Diabetes ◽

Burkina Faso ◽

Association Studies ◽

Statistical Significance ◽

Black Population ◽

Allelic Exclusion ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

African Black

Recent genome-wide association studies and replication analyses have reported the association of variants of the exostosin- 2 gene (EXT2) and risk of type 2 diabetes (T2D) in some populations, but not in others. This study aimed to characterize the variants rs1113132, rs3740878 and rs11037909 of EXT2 and to determine the existence of a possible correlation with T2D in Burkina Faso. It is a case-control study undertaken in Burkina Faso in the city of Ouagadougou at the Hospital of Saint Camille of Ouagadougou from December 2014 to June 2015. It relates to 121 type 2 diabetes cases and 134 controls. The genotyping of these polymorphisms was done by real-time PCR using the allelic exclusion method with TaqMan probes. The minor allele frequencies (MAFs) was almost identical in diabetic and control subjects for the all three Single Nucleotide Polymorphisms (SNPs) with no statistical significance, p>0.05: rs1113132 (OR=0.89; p=0.82); rs11037909 (OR=0.89; p=0.74) and rs3740878 (OR=1.52; p=0.42). None of the three polymorphisms studied was associated with the risk of DT2. However, an association between the BMI, age and type 2 diabetes was noted. The variants of EXT2 would not be associated to the risk of T2D in the African black population of Burkina Faso.

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Bayesian network analysis of plasma microRNA sequencing data in patients with venous thrombosis

European Heart Journal Supplements ◽

10.1093/eurheartj/suaa008 ◽

2020 ◽

Vol 22 (Supplement_C) ◽

pp. C34-C45 ◽

Cited By ~ 3

Author(s):

Florian Thibord ◽

Gaëlle Munsch ◽

Claire Perret ◽

Pierre Suchon ◽

Maguelonne Roux ◽

...

Keyword(s):

Venous Thrombosis ◽

Association Studies ◽

Statistical Significance ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Sequencing Data ◽

New Associations ◽

Significance Threshold ◽

The Impact ◽

Plasma Mirna

Abstract MicroRNAs (miRNAs) are small regulatory RNAs participating to several biological processes and known to be involved in various pathologies. Measurable in body fluids, miRNAs have been proposed to serve as efficient biomarkers for diseases and/or associated traits. Here, we performed a next-generation-sequencing based profiling of plasma miRNAs in 344 patients with venous thrombosis (VT) and assessed the association of plasma miRNA levels with several haemostatic traits and the risk of VT recurrence. Among the most significant findings, we detected an association between hsa-miR-199b-3p and haematocrit levels (P = 0.0016), these two markers having both been independently reported to associate with VT risk. We also observed suggestive evidence for association of hsa-miR-370-3p (P = 0.019), hsa-miR-27b-3p (P = 0.016) and hsa-miR-222-3p (P = 0.049) with VT recurrence, the observations at the latter two miRNAs confirming the recent findings of Wang et al. Besides, by conducting Genome-Wide Association Studies on miRNA levels and meta-analyzing our results with some publicly available, we identified 21 new associations of single nucleotide polymorphisms with plasma miRNA levels at the statistical significance threshold of P < 5 × 10−8, some of these associations pertaining to thrombosis associated mechanisms. In conclusion, this study provides novel data about the impact of miRNAs’ variability in haemostasis and new arguments supporting the association of few miRNAs with the risk of recurrence in patients with venous thrombosis.

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Circulating Levels of CILP2 Are Elevated in Coronary Heart Disease and Associated with Atherosclerosis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/1871984 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Wenjing Hu ◽

Ke Li ◽

Hongdong Han ◽

Shan Geng ◽

Baoyong Zhou ◽

...

Keyword(s):

Insulin Resistance ◽

Coronary Heart Disease ◽

Heart Disease ◽

Association Studies ◽

Foam Cell Formation ◽

Genome Wide Association Studies ◽

Model Assessment ◽

Western Blots ◽

Cd36 Expression

Background and Objectives. Genome-wide association studies (GWAS) have shown that cartilage intermediate layer protein 2 (CILP2) is associated with blood lipid levels and coronary heart disease (CHD). However, no study has reported whether CILP2 is related to atherosclerosis in humans. The purpose of the current study is to identify the associations between CILP2 and atherosclerosis in vitro and in vivo. Methods and Results. Circulating CILP2 levels (measured by ELISA) were compared to various insulin resistance- and atherosclerosis-related parameters in normal subjects and newly diagnosed CHD patients. THP-1 cells were cultured and treated with indicated stimulators. Western blots and RT-PCR were performed to examine protein and mRNA expressions. The results showed that there were significantly higher circulating CILP2 levels in CHD patients relative to healthy controls. Circulating CILP2 correlated positively with waist-hip ratio (WHR), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HbA1c, homeostasis model assessment of insulin resistance (HOMA-IR), and Gensini scores. In an in vitro study, we found that CILP2 increased oxidatively modified LDL-stimulated lipid accumulation in THP-1 macrophages via the upregulation of CD36 expression. Inhibition of PPARγ signaling eliminated the CILP2 regulation of CD36 expression in THP-1 macrophages. CILP2 positively regulated CD36 transcription through PPARγ-mediated action on two peroxisome-proliferator-responsive elements (PPREs) binding sites of CD36 promoter, PPRE-G, and PPRE-J. Conclusions. Our findings have uncovered a novel role for CILP2 in lipid uptake and foam cell formation. This role is mediated by CD36 through the activation of PPARγ pathway.

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Commonly Studied Single-Nucleotide Polymorphisms and Breast Cancer: Results From the Breast Cancer Association Consortium

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djj374 ◽

2006 ◽

Vol 98 (19) ◽

pp. 1382-1396 ◽

Cited By ~ 186

Author(s):

Keyword(s):

Breast Cancer ◽

Single Nucleotide Polymorphisms ◽

Association Studies ◽

Statistical Tests ◽

Statistical Significance ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Odds Ratios ◽

Single Nucleotide ◽

Breast Cancer Association Consortium

Abstract Background: The Breast Cancer Association Consortium (BCAC) is an international collaboration that was established to provide large sample sizes for examining genetic associations. We conducted combined analyses on all single-nucleotide polymorphisms (SNPs) whose associations with breast cancer have been investigated by at least three participating groups. Methods: Data from up to 12 studies were pooled for each SNP ( ADH1C I350V, AURKA F31I, BRCA2 N372H, CASP8 D302H, ERCC2 D312N, IGFBP3 −202 c > a , LIG4 D501D, PGR V660L, SOD2 V16A, TGFB1 L10P, TP53 R72P, XRCC1 R399Q, XRCC2 R188H, XRCC3 T241M, XRCC3 5′ UTR, and XRCC3 IVS7-14). Genotype frequencies in case and control subjects were compared, and genotype-specific odds ratios for the risk of breast cancer in heterozygotes and homozygotes for the rare allele compared with homozygotes for the common allele were estimated with logistic regression. Statistical tests were two-sided. Results: The total number of subjects for analysis of each SNP ranged from 12 013 to 31 595. For five SNPs— CASP8 D302H, IGFBP3 −202 c > a , PGR V660L, SOD2 V16A, and TGFB1 L10P—the associations with breast cancer were of borderline statistical significance ( P = .016, .060, .047, .056, and .0088 respectively). The remaining 11 SNPs were not associated with breast cancer risk; genotype-specific odds ratios were close to unity. There was some evidence for between-study heterogeneity ( P <.05) for four of the 11 SNPs ( ADH1C I350V, ERCC2 D312N, XRCC1 R399Q, and XRCC3 IVS5-14). Conclusion: Pooling data within a large consortium has helped to clarify associations of SNPs with breast cancer. In the future, consortia such as the BCAC will be important in the analysis of rare polymorphisms and gene × gene or gene × environment interactions, for which individual studies have low power to identify associations, and in the validation of associations identified from genome-wide association studies.

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Multivariate Analysis of Potential Pleiotropic Genes For Breast, Ovarian And Cervical Cancers Using Gene-Based Association Analysis

10.21203/rs.3.rs-695526/v1 ◽

2021 ◽

Author(s):

XiaoCan Jia ◽

Nian Shi ◽

Yu Feng ◽

Huili Zhu ◽

Yuping Wang ◽

...

Keyword(s):

Network Analysis ◽

Association Studies ◽

Statistical Significance ◽

Enrichment Analysis ◽

Biological Pathways ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Ppi Network ◽

Cervical Cancers ◽

Protein Protein Interaction

Abstract Although genome-wide association studies (GWAS) have a dramatic impact on susceptibility locus discovery in gynecological malignancies, the single nucleotide polymorphisms (SNPs) identified by this prevailing univariate approach only explain a small percentage of heredity. The extensive previous studies have repeatedly shown breast, ovarian and cervical cancers have common genetic mechanisms and the overlapping pathophysiological pathways. Novel multivariate analytical methods are necessary to identify shared pleiotropic genes. In this study, a total of 40,859 SNPs mapped in 11,597 gene regions were performed to identify potential common variants by using metaCCA and VEGAS2 analysis. Gene enrichment and protein-protein interaction (PPI) network analysis were used to explore potential biological pathways and connectivity. After metaCCA analysis, 4,203 SNPs (P<1.22×10−6) and 1,886 pleotropic gene (P<4.31×10−6) were identified. By screening the results of gene-based P-values, the existence of 3 confirmed pleiotropic genes and 16 novel genes that achieved statistical significance in the metaCCA analysis and were also associated with at least one cancer in the VEGAS2 analysis were identified. The enrichment analysis showed the biological pathways of these genes were mainly enriched in 4 signaling pathways and 11 differentially expressed genes were found to encode interacting proteins in PPI network analysis. Altogether, we identified novel genetic variants of breast, ovarian and cervical cancers and provided evidence of biological functions which developed new insights for the diagnosis and treatment of these cancers.

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Genetics of fasting indices of glucose homeostasis using GWIS unravels tight relationships with inflammatory markers

10.1101/496802 ◽

2018 ◽

Author(s):

Iryna O. Fedko ◽

Michel G. Nivard ◽

Jouke-Jan Hottenga ◽

Liudmila Zudina ◽

Zhanna Balkhiyarova ◽

...

Keyword(s):

Insulin Resistance ◽

Inflammatory Markers ◽

Cell Function ◽

Association Studies ◽

Genetic Relationships ◽

Genetic Correlations ◽

Genome Wide Association Studies ◽

Model Assessment ◽

Plasminogen Activator Inhibitor 1 ◽

Genome Wide

AbstractPurposeHomeostasis Model Assessment of β-cell function and Insulin Resistance (HOMA-B/-IR) indices are informative about the pathophysiological processes underlying type 2 diabetes (T2D). Data on both fasting glucose and insulin levels are required to calculate HOMA-B/-IR, leading to underpowered Genome-Wide Association studies (GWAS) of these traits.MethodsWe overcame such power loss issues by implementing Genome-Wide Inferred Statistics (GWIS) approach and subsequent dense genome-wide imputation of HOMA-B/-IR summary statistics with SS-imp to 1000 Genomes project variant density, reaching an analytical sample size of 75,240 European individuals without diabetes. We dissected mechanistic heterogeneity of glycaemic trait/T2D loci effects on HOMA-B/-IR and their relationships with 36 inflammatory and cardiometabolic phenotypes.ResultsWe identified one/three novel HOMA-B (FOXA2)/HOMA-IR (LYPLAL1, PER4,PPP1R3B) loci. We detected novel strong genetic correlations between HOMA-IR/-B and Plasminogen Activator Inhibitor 1 (PAI-1, rg=0.92/0.78, P=2.13×10-4/2.54×10-3). HOMA-IR/-B were also correlated with C-Reactive Protein (rg=0.33/0.28, P=4.67×10-3/3.65×10-3). HOMA-IR was additionally correlated with T2D (rg=0.56, P=2.31×10-9), glycated haemoglobin (rg=0.28, P=0.024) and adiponectin (rg=-0.30, P=0.012).ConclusionUsing innovative GWIS approach for composite phenotypes we report novel evidence for genetic relationships between fasting indices of insulin resistance/beta-cell function and inflammatory markers, providing further support for the role of inflammation in T2D pathogenesis.

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Autocrine IGF2 programmes β-cell plasticity under conditions of increased metabolic demand

Scientific Reports ◽

10.1038/s41598-021-87292-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ionel Sandovici ◽

Constanze M. Hammerle ◽

Sam Virtue ◽

Yurena Vivas-Garcia ◽

Adriana Izquierdo-Lahuerta ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Homeostasis ◽

Association Studies ◽

Susceptibility Gene ◽

Chow Diet ◽

Genome Wide Association Studies ◽

Cell Plasticity ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells

AbstractWhen exposed to nutrient excess and insulin resistance, pancreatic β-cells undergo adaptive changes in order to maintain glucose homeostasis. The role that growth control genes, highly expressed in early pancreas development, might exert in programming β-cell plasticity in later life is a poorly studied area. The imprinted Igf2 (insulin-like growth factor 2) gene is highly transcribed during early life and has been identified in recent genome-wide association studies as a type 2 diabetes susceptibility gene in humans. Hence, here we investigate the long-term phenotypic metabolic consequences of conditional Igf2 deletion in pancreatic β-cells (Igf2βKO) in mice. We show that autocrine actions of IGF2 are not critical for β-cell development, or for the early post-natal wave of β-cell remodelling. Additionally, adult Igf2βKO mice maintain glucose homeostasis when fed a chow diet. However, pregnant Igf2βKO females become hyperglycemic and hyperinsulinemic, and their conceptuses exhibit hyperinsulinemia and placentomegalia. Insulin resistance induced by congenital leptin deficiency also renders Igf2βKO females more hyperglycaemic compared to leptin-deficient controls. Upon high-fat diet feeding, Igf2βKO females are less susceptible to develop insulin resistance. Based on these findings, we conclude that in female mice, autocrine actions of β-cell IGF2 during early development determine their adaptive capacity in adult life.

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